'Management'of'hypoglycemia'in' Late'preterm'and'term'infants'

Consensus'Clinical'Guidelines'for'Screening'&'Management'of'Hypoglycemia'in' Late'Preterm'and'Term'Infants'(≥'34'weeks'GA)' UCSF'NCNC'(Northern'California'Neonatology'Consortium)' ' PART'I:'Background'' •% Risk'factors'for'neonatal'hypoglycemia' o% Inadequate%glycogen%stores' !% Small%for%gestational%age%(SGA)' !% Intrauterine%growth%restriction%(IUGR)' !% Prematurity%(<37%weeks%gestational%age)' !% PostVterm%gestation%(≥42%weeks%gestational%age)' o% Increased%glucose%utilization' !% Large%for%gestational%age%(LGA)' !% Infant%of%a%diabetic%mother%(IDM)' •% Includes%mothers%with%preVexisting%diabetes%(DM1%or%2)%or% gestational%diabetes%(GDMA1%=%dietVcontrolled%or%GDMA2%=% medicationVcontrolled)' !% Conditions%which%increase%metabolic%demand:%sepsis,%encephalopathy,% HIE,%perinatal%stroke,%seizures,%hypothermia,%prematurity,%polycythemia,% hemolytic%disease,%metabolic%disease,%respiratory%distress,%endocrine% abnormalities,%congenital%heart%disease,%maternal%substance%use' o% Hyperinsulinemia' !% LGA' !% IUGR' !% IDM' !% Certain%genetic/metabolic%conditions%(e.g.%BeckwithVWeidemann% Syndrome)' •% Sequelae'of'neonatal'hypoglycemia' o% Neurodevelopmental%Sequelae' !% Association%with%worse%cognitive%and%motor%performance%on% developmental%testing%at%18%months,%3%years,%5%yearsa%lower%school% achievement%in%children%at%4th%grade' !% NOTE:%recurrent%episodes%of%hypoglycemia%are%more%predictive%of%longV term%sequelae' !% CAVEAT:%causality%has%not%been%determined%for%these%associations,%nor% effectiveness%/%safety%of%screening%and%intervention%to%raise%glucose%levels' ' PART'II:'Definition'of'hypoglycemia' •% Definition%of%hypoglycemia' o% “Plasma%glucose%concentration%below%which%normal%brain%function%cannot%occur”' o% Published%thresholds%for%diagnosing%hypoglycemia:' !% NOTE:%difficult%to%define%a%single%blood%glucose%concentration%that% warrants%intervention%in%every%neonate.%Published%literature%and% guidelines%primarily%rely%on%normative%values%since%defining%hypoglycemia% based%on%presence/absence%of%sequelae%or%performing%prospective% clinical%trials%is%impossible.' !% NOTE:%units%for%all%glucose%values%are%in%mg/dL'

UCSF%NC2%(Northern%CA%Neonatology%Consortium).%Originated%5/2014.%Edited%9/2015,%5/2018.% Approved%by%UCSF%ICN%Patient%Safety%Committee:%7/2018% Approved%by%UCSF%Pharmacy%and%Therapeutics%Committee:%8/2018! 1% !% Alkalay,%et%al.%(2006)%V%estimate%of%5th%percentile%(breast%and%formula%fed% infants):%' •% 1V2hrs:%27' •% 3V23hrs:%40' •% 24V47hrs:%41' •% 48V72hrs:%48' !% Cornblath%&%Ichord%(2000)%V%formula%fed%infants:' •% All%infants%<20V25' •% First%24hrs%<30V35%(sick%<45V50)' •% >24hrs%<40V50' !% Canadian%Pediatric%Society%(2004):%' •% <32%2hrs%postVfeed' •% <36%postVsubsequent%feed' !% American%Academy%of%Pediatrics%(AAP)%(2011):' •% BirthV4hrs%<25%(target%>40)' •% 4V24hrs%<35%(target%>45)' !% Academy%of%Breastfeeding%Medicine%(ABM)%(2014):' •% <20V25%requires%intervention%(goal%>40)' •% UCSF%NCNC%consensus%thresholds%for%hypoglycemia:' o% NOTE:%values%based%primarily%on%2011%AAP%Clinical%Report' o% Target/goal%neonatal%glucose:%' !% ≥%45%prior%to%routine%feeds%@%0V24%hours%after%birth' !% ≥%50%prior%to%routine%feeds%@%>24%hours%after%birth' ' PART'III:'Screening'of'asymptomatic,'at'risk'infants' •% Screening%criteria%for%asymptomatic,%wellVappearing,%at%risk%infants' o% IDM%(preVexisting%maternal%diabetes,%GDMA1,%GDMA2)' o% Growth%Restricted%or%Macrosomic%(defined%by%average%of%male%&%female%weights% on%Fenton%2013%intrauterine%growth%curves):' !% Growth%Restricted%(<5th%)' !% Macrosomic%(>97.5th%)%%' !% NOTE:%use%of%a%strict%birthweight%criteria%for%all%term%infants%is%no%longer% recommended%(e.g.%<2500,%>4000)' ' 37P37+6/7' 38P38+6/7' 39P39+6/7' 40P40+6/7' >41' weeks' weeks' weeks' weeks' weeks' Growth'restricted'(<5th%)' 2280'g' 2470'g' 2650'g' 2820'g' 3000'g' Macrosomic'(>97.5th%)' 3950'g' 4180'g' 4400'g' 4630'g' 4880'g' o% Late%preterm%(34V37%weeks)' o% Post%term%(≥42%weeks)' o% Additional%consideration:%neonates%with%conditions%known%to%be%associated%with% secondary%hypoglycemia%(i.e.%polycythemia,%sepsis)%should%also%be%considered% for%hypoglycemia%screening' •% Method%of%screening' o% Glucometer' !% NOTE:%accuracy%in%low%range%depends%on%make/model%of%glucometera% newer%meters%are%more%accurate%in%low%range'

UCSF%NC2%(Northern%CA%Neonatology%Consortium).%Originated%5/2014.%Edited%9/2015,%5/2018.% Approved%by%UCSF%ICN%Patient%Safety%Committee:%7/2018% Approved%by%UCSF%Pharmacy%and%Therapeutics%Committee:%8/2018! 2% !% NOTE:'sample%should%be%drawn%from%warmed%heel%stick%%' o% Confirm%low%values%with%iSTAT%if%available%or%stat%blood%sample%sent%to% laboratory%' o% NOTE:%Consider%initiating%treatment%for%hypoglycemia%prior%to%confirmatory% testing%if%waiting%for%laboratory%result%will%delay%treatment%excessively%' •% Timing%of%screening' o% General%principles:' !% Initial%screen%after%first%(breast)feeding%(by%~1%hour%after%birth)' !% More%frequent%screening%in%first%2V4%hours%of%life,%then%pre$prandial% screening%that%is%roughly%linked%to%feeding%schedule' !% Stop%screening%at%12%hours%for%macrosomic,%IDM%infants%(very%low%risk%of% late%hypoglycemia)' !% Continue%screening%until%24%hours%for%growth%restricted,%late%preterm% infants%(greater%risk%of%late%hypoglycemia)' !% Consider%36%hour%screening%for%growth%restricted,%late%preterm%infants%if% glucoses%consistently%<45%in%first%24%hours%after%birth' o% Time%points%for%Glucose%Screening:%~1,%2,%4,%6,%9,%12,%24%hours%unless% intervention%is%required' o% “Early%exit”:%consider%discontinuing%glucose%screening%prior%to%completion%of%all% time%points%in%asymptomatic%infants%with%“stable”,%“normal”%glucoses%in%the%first% 24%hours%after%birth:%%' !% Glucoses%>45%on%3%occasions' !% Repeat%one%preVprandial%glucose%measurement%at%24%hours%after%birth%for% growth%restricted,%late%preVterm%infants' !% NOTE:%these%recommendations%are%consensusVbaseda%no%specific% evidence%is%currently%available%to%support%these%recommendations' ' PART'IV:'Management'of'asymptomatic'infants' •% See%APPENDIX%2%for%summary%clinical%pathway%/%decision%tree%(ASYMPTOMATIC)' •% Intervention%thresholds%(see%PART%II%above%for%details):' o% NOTE:%treatment%thresholds%vary%at%0V4%hours%and%4V24%hours%after%birth%to% reflect%changing%physiology%/%normal%values%during%transition%to%postnatal%life' •% Treatment:' o% See%algorithm%for%full%work%flow%and%indications%for%treatment' o% Oral%feeding%(breast%or%formula):' !% Method:' •% Breastfeeding' o% ReVcheck%glucose%1%hour%after%initiation%of%feeding' o% Repeat%breastfeeding%if%glucose%remains%below%thresholda%if% glucose%remains%below%threshold%after%>2%breastfeeding% attempts,%then%consider%oral%formula%supplementation%' o% Oral%administration%of%expressed%maternal%breastmilk%(MBM)% is%also%an%acceptable%form%of%treatment' •% Formula%' o% Use%protein%hydrolysate%formula%(i.e.%Alimentum,% Nutramigen,%Pregestimil)%preferentially%if%available%to%reduce% exposure%to%cow%milk%protein' UCSF%NC2%(Northern%CA%Neonatology%Consortium).%Originated%5/2014.%Edited%9/2015,%5/2018.% Approved%by%UCSF%ICN%Patient%Safety%Committee:%7/2018% Approved%by%UCSF%Pharmacy%and%Therapeutics%Committee:%8/2018! 3% !% 1V4%hours%"%10V20%mL%' !% 4V24%hours%"%15V30%mL%' o% ReVcheck%glucose%1%hour%after%initiation%of%feeding' o% If%glucose%remains%below%threshold%after%>2%oral%feedings,% then%consider%IV%treatment' o% Oral%glucose%gel' !% Method:' •% Glucose%(Dextrose)%40%%gel%' •% Administer%0.5ml/kg%with%max%of%2.5%mL' •% Dry%newborn’s%mouth%with%2x2%gauze' •% Massage%the%ordered%amount%of%glucose%gel%using%gloved% fingertips%into%the%buccal%mucosa,%instilling%no%more%than%0.5ml%into% each%cheek%at%a%time' !% Important%considerations' •% MAXIMUM%of%THREE%doses%per%24%hours%of%oral%glucose%gel% before%proceeding%to%IV%treatment.%%' •% Consider%IV%treatment%prior%to%3rd%dose%of%oral%glucose%if%infant%is% not%having%sequentially%rising%glucoses%in%response%to%oral%therapy.%%' o% IV%treatment:' !% Indications:' •% Glucoses%not%responding%appropriately%to%oral%glucose%and%feeding% therapy' •% Persistent%hypoglycemia%after%3%doses%of%oral%glucose%gel' •% Any%glucose%<35%after%5%HOL' !% Method:' •% D10W%2V3%ml/kg%IV%bolus,%followed%by:' •% D10W%@%80%ml/kg/day%(3.5%ml/kg/hr)' o% Glucose%infusion%rate%(GIR)%5.5%mg/kg/min' o% Increase%D10W%in%increments%of%20%ml/kg/day%(0.8%ml/kg/hr)% if%needed%for%persistent%hypoglycemia' o% NOTE:%If%total%fluid%administration%exceeds%150%ml/kg/day% (6.25%ml/kg/hr),%consider%increasing%dextrose%concentration% to%D12.5%rather%than%IV%rate%to%avoid%fluid%overload' •% Continue%IV%treatment%until%glucose%levels%are%stable%>50,%then% wean%IV%gradually' •% NOTE:%For%any%infant%with%persistent%hypoglycemia,'consider%further%evaluation%for% underlying%etiology%in%parallel%with%treatment%% ' PART'V:'Management'of'symptomatic'infants' •% See%APPENDIX%3%for%summary%clinical%pathway%/%decision%tree%(SYMPTOMATIC)' •% Symptoms%of%hypoglycemia%may%include:' o% General%symptoms:' !% Abnormal%cry,%poor%feeding,%hypothermia,%diaphoresis' o% Neurologic%symptoms:' !% Tremors,%jitteriness,%hypotonia,%irritability,%highVpitched%cry,%lethargy,% seizures'

UCSF%NC2%(Northern%CA%Neonatology%Consortium).%Originated%5/2014.%Edited%9/2015,%5/2018.% Approved%by%UCSF%ICN%Patient%Safety%Committee:%7/2018% Approved%by%UCSF%Pharmacy%and%Therapeutics%Committee:%8/2018! 4% o% Cardiorespiratory%disturbances:' !% Cyanosis,%pallor,%tachypnea,%apnea,%cardiac%arrest' •% Differentiation%of%“concerning”%(“definite”)%versus%“possible”%symptoms%of%hypoglycemia:%' o% “CONCERNING”:%seizure,%lethargy/poorly%responsive,%hypotonia,%apnea,% cyanosis%' o% “POSSIBLE”:%jitteriness,%tremors,%irritability,%exaggerated%Moro%reflex,%highV pitched%cry,%poor%feeding,%excessive%sleepiness/drowsiness' •% Thresholds%for%intervention%&%treatment:' o% “CONCERNING”%(regardless%of%age)% !% <45%"%IV%treatment%% !% Use%IV%treatment%method%from%PART%IV%above% !% If%symptoms%do%not%resolve%after%glucose%>50,%pursue%workVup%of%other% potential%causes%of%symptoms% !% Reasonable%to%give%small%aliquots%of%oral%glucose%gel%(0.5%mL%at%a%time)% while%obtaining%IV%access% o% “POSSIBLE”%(regardless%of%age)% !% 35V45%"%oral%treatment%(breastfeeding%or%formula)%+%oral%glucose%gel% !% <35%"%IV%treatment%after%one%attempt%at%oral%feeding% !% Use%IV%or%oral%treatment%method%from%PART%IV%above% !% If%symptoms%do%not%resolve%after%glucose%>50,%pursue%workVup%of%other% potential%causes%of%symptoms% •% NOTE:%For%any%infant%with%persistent%hypoglycemia,'consider%further%evaluation%for% underlying%etiology%in%parallel%with%treatment.%%Strongly%consider%Neonatologist% involvement%and%Endocrine%consultation%prior%to%considering%glucagon,%octreotide,%or% other%therapies.%% ' PART'VI:'NICU'and'Special'Care'/'Transitional'Care'Nursery' •% Treatment%thresholds%and%treatment%methods%are%different%for%infants%in%these%higher% level%care%settingsa%consult%neonatology%for%recommendations' %

UCSF%NC2%(Northern%CA%Neonatology%Consortium).%Originated%5/2014.%Edited%9/2015,%5/2018.% Approved%by%UCSF%ICN%Patient%Safety%Committee:%7/2018% Approved%by%UCSF%Pharmacy%and%Therapeutics%Committee:%8/2018! 5% References' ' Adamkin%DH%&%AAP%COFN.%2011.%Clinical%Report%–%Postnatal%Glucose%Homeostasis%in% LateVPreterm%and%Term%Infants.%Pediatrics.%127,3:%575V579.% % Alkalay,%et%al.%2006.%Population%metaVanalysis%of%low%plasma%glucose%thresholds%in%fullVterm% normal%newborns.%Am%J%Perinatol.%23:%115V119.% % Canadian%Pediatric%Society.%2004.%Screening%guidelines%for%newborns%at%risk%for%low%blood% glucose.%Pediatr%Child%Health.%9:%723V729.% % Cornblath,%M%&%Ichord,%R.%2000.%Hypoglycemia%in%the%neonate.%Sem%Perinatol.%24:%136V% 149.% % Harris,%et%al.%2012.%Incidence%of%neonatal%hypoglycemia%in%babies%identified%as%at%risk.%J% Pediatr.%161:%787V791.% % Kaiser%JR,%et%al.%2015.%Association%between%Transient%Newborn%Hypoglycemia%and%Fourth% Grade%Achievement%Test%Proficiency.%JAMA.%E1V9.% % McKinlay%C%&%J%Harding.%2015.%Revisiting%Transitional%Hypoglycemia:%only%time%will%tell% (opinion).%JAMA.%E1V2.% % Rozance,%PJ%&%Hay,%WW.%2006.%Hypoglycemia%in%newborn%infants:%Features%associated% with%adverse%outcomes.%Biol%Neonate.%90:%74V86.% % Rozance,%PJ.%2014.%Update%on%neonatal%hypoglycemia.%Curr%Opin%Endocrinol%Diabetes% Obes.%21:%45V50.% % Stanley,%et%al.%2015.%ReVevaluating%“transitional%neonatal%hypoglycemia”:%mechanism%and% implications%for%management.%J%Pediatr.%166,6:%1520V5.% % Stieren,%Emily%&%Fernando%Gonzalez.%Clinical%Consensus%Conference:%Neonatal% Hypoglycemia.%UCSF.%May%26,%2015.% % Thornton,%et%al.%2015.%Recommendations%from%the%Pediatric%Endocrine%Society%for% evaluation%and%management%of%persistent%hypoglycemia%in%neonates,%infants,%and%children.% J%Pediatr.%167,2:%238V45.% % Wight,%et%al.%2014.%ABM%Clinical%Protocol%#1:%Guidelines%for%blood%glucose%monitoring% and%treatment%of%hypoglycemia%in%term%and%lateVpreterm%neonates.%Breastfeeding%Med.%9:% 173V179.% % %

UCSF%NC2%(Northern%CA%Neonatology%Consortium).%Originated%5/2014.%Edited%9/2015,%5/2018.% Approved%by%UCSF%ICN%Patient%Safety%Committee:%7/2018% Approved%by%UCSF%Pharmacy%and%Therapeutics%Committee:%8/2018! 8% APPENDIX'2:'Screening'&'Management'of'Neonatal'Hypoglycemia'in' ASYMPTOMATIC'infants'≥'34wks'GA'

' UCSF%NC2%(Northern%CA%Neonatology%Consortium).%Originated%5/2014.%Edited%9/2015,%5/2018.% Approved%by%UCSF%ICN%Patient%Safety%Committee:%7/2018% Approved%by%UCSF%Pharmacy%and%Therapeutics%Committee:%8/2018! 9% APPENDIX' 3:' Screening' &' Management' of' Neonatal' Hypoglycemia' in' SYMPTOMATIC'infants'≥'34wks'GA' '